Quinuclidylalkyl esters

ABSTRACT

The compounds are quinuclidylalkyl esters which are useful as chemical intermediates and possess an anti-Parkinsonism activity. A representative compound is 2-quinuclidylmethyl phenylcyclopentylglycolate.

United States Patent [19] Judd et al. 1 Apr. 3, 1973 [54] QUINUCLIDYLALKYL ESTERS 3,405,134 10/1968 Judd ..260/293.53

75 Inventors: Claude I. Judd, Mequon; Wallace K. OTHER PUBLICATIONS n Mllwaukee both of Mashkovsky, Proc. of the First lntfPharm. Meeting, [73] Assign'ee: Colgate-Palmolive Company, New VOL PP- 359 to 6, 1963, Published y Pergamon York, N.Y, Press, London [22] Filed: Aug. 18, 1965 Primary Exqminer-Lela'nd A. Sebastian NOJ Att0rneyT. F. Kryshak and M. YOurlgs [57] ABSTRACT [52] U.S.Cl .....260/293.53, 424/267 The compounds are quinuclidylalkyl esters which are 1].. CL. useful as chemical intermediates and Po an anti [58] Fleld of Search ..260/294.3 A, 293.53 parkinsonism activity A representative compound is 2-quinuclidylmethyl phenylcyclopentylglycolate.

[56] References Cited UNiTED STATES PATENTS l/l964 Planfetti et al. ..260/293.53

8 Claims, No Drawings l QUINUCLIDYLALKYL ESTERS This invention relates to novel derivatives of quinuclidyl alcohols. More particularly, it relates to novel esters of 2-quinuclidylalkanols and non-toxic salts thereof. I r

The compounds of the present invention may be represented by the following formula:

wherein R and R are selected from the group consisting of hydrogen, lower alkyl such as methyl, ethyl, isopropyl and butyl, cycloalkyl such as cyclopentyl or cyclohexyl, aralkyl such as benzyl, and aryl such as phenyl or nuclear-substituted phenyl, and X is selected from hydrogen and hydroxyl.

The novel esters of the present invention may be prepared by treating Z-quinuclidylmethanol with an ester of a desired acid, such as a lower alkyl ester, in the presence of an alkaline catalyst, such as sodium methoxide. The reaction is preferably carried out in an inert solvent, such as n-heptane or xylene, at reflux temperatures until the theoretical amount of alcoholic by-product which distills over has been collected. The reaction mixture is filtered while still warm and the filter bed washed with chloroform. The organic filtrates are then washed with water and dried. Tl-le solvent is evaporated off under pressure to obtain the crude ester which may be purified by conventional means.

Representative of the esters which can be employed as starting materials are the lower esters of benzilic acid such as methyl benzilate, the lower esters of diphenylacetic acid, and the esters of substituted gylcolic acids such as methyl phenylcyclopentylglycolate.

The process may be representedas follows:

where Y is a lower alkyl of l to 4carbon atoms and all other symbols have their assigned values. The 2-quinuclidylmethanol may be prepared from the corresponding 2-quinuclidylcarboxylic .acid ester by treating the ester with sodium in absolute alcohol as described by V. Prelog and E. Cerkovnikov, Ann., 545,

Representative of the novel esters which can be prepared in the previously described manner are the following:

Z-quinuclidylmethyl benzilate, 2-quinuclidylm ethyl diphenylacetate, and 2-quinuclidylmethyl phenylcyclopentylglycolate. The novel esters form acid additionsalts with organic and inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and the like. In addition, they form quaternary salts with .quaternizing agents such as methyl bromide, benzyl chloride and the like.

pounds is generally combined with a suitable pharmaceutical carrier and made into unit dosage forms. These dosage forms may be made for either oral or parenteral administration.

Pharmaceutical carriers which are either liquid or solid may be employed. The preferred liquid carrier is water. However, in the event the compound is not soluble or miscible in water, an organic solvent such as ethylene glycol may be employed. Flavoring materials may be included if desired.

and talc can be utilized to form powders. These powders can be used as such or-can be tableted or used to fill gelatin capsules. Suitable lubricants such-as magnesium stearate, binders such as gelatin, and disintegrating agents such as sodium carbonate incombination with citric acid may be employed in the formation of the tablets.

vUnit dosage forms such as tablets and capsules may contain any suitable predetermined amount of one or more of the active ingredients as a non-toxic salt and a may be administered one or more at -a time at regular intervals. Such unit dosage forms, however, should generally contain a concentration of 0.1 to 10 percent by weight of one or more of the active agents. Such unit dosage forms should advisably contain about 5 to mg. of the active ingredients.

A typical tablet may have the following composition:

mg. l) Z-quinuclidylmethyl benzilate hydrochloride l0 (2) Starch U.S.P. 57 (3) Lactose U.S.P. 73 (4) Talc U.S.P. 9 (5 Stearic acid 7 6' Powders (l), (2) and (3) are slugged, then granulated, mixed with (4) and (5) and tableted.

Capsules may be prepared by filling No. 3 bar gelatin capsules with the following ingredients:

' mg. l 2-quinuclidylmethyl benzilatc hydrochloride 20 (2) Lactose U.S.P. 200 (3)Starch U.S.P. lo (4) Talc .U.S.P.- 8

The oral route is generally preferred for administering the compounds of this invention. However, other routes of administrationsuch as parenteral may be employed.

' The following examples are presented to illustrate this invention:

Solid pharmaceutical carriers such as starch,sugar I EXAMPLE 1 Z-Quinuclidylmethyl benzilate hydrochloride A mixture of 0.0355 mole of 2-quinuclidylmethanol, 0.0355 mole of methyl benzilate, 250 ml. n-heptane and a freshly prepared solution of 0.1 g. sodium in ml. methanol is stirred at reflux as 7.8 ml. methanol distills off and is collected in a Dean-Stark separator. The reaction mixture is filtered warm and the filter bed washed with chloroform. The organic filtrates are washed twice with 50 ml. portions of water and dried' briefly over anhydrous potassium carbonate. The solvent is evaporated under reduced pressure. The 7.2 g. yellow solids remaining are dissolved in ethanol and acidified with anhydrous hydrogen chloride. The solids which precipitate are collected by filtration and recrystallized from acetonitrile yielding 2-quinuclidylmethyl benzilate hydrochloride, m.p. 262 C.

Anal. Calcd. for C H ClNO C, 68.12; H, 6.75; N, 3.61; Cl, 9.14. Found: C, 68.24; H, 6.74; N, 3.61; C], 9.27.

EXAMPLE 2 Z-Quinuclidylmethyl diphenylacetate hydrochloride The procedure of Example 1 is repeated employing methyl diphenylacetate in place of the. methyl benzilate. The compound obtained is Z-quinuclidylmethyl diphenylacetate hydrochloride.

EXAMPLE 3 2-Quinuclidylmethyl phenylcyclopentylglycolate The procedure of Example 1 is repeated employing methyl phenylcyclopentylglycolate in place of the methyl benzilate. The compound obtained is 2-quinuclidylmethyl phenylcyclopentylglycolate.

I claim:

1. A compound selected from the group consisting of compounds of the formula wherein R is selected from alkyl, cycloalkyl, aralkyl and aryl, R is selected from aryl and aralkyl and X is selected from hydrogen and hydroxyl, and pharmaceu- 

2. A compound of claim 1 in which R and R1 are aryl.
 3. A compound of claim 1 in which R and R1 are phenyl.
 4. A compound of claim 1 in which R and R1 are aryl and X is hydroxyl.
 5. A compound of claim 1 in which R is lower alkyl and R1 is aryl.
 6. 2-quinuclidylmethyl benzilate.
 7. 2quinuclidylmethyl diphenylacetate.
 8. 2. -quinuclidylmethyl phenylcyclopentylglycolate. 